Professional Documents
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School of Pharmacy
University of North Cam Una
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Volume 9. A C T I V A T E D C H A R C O A L : A N T I D O T A L A N D OTHER
M E D I C A L USES, David O. Cooney
Volume 1 1 . P H A R M A C E U T I C A L A N A L Y S I S : M O D E R N METHODS
(in two parts), edited by James i/V. Munson
Volume 12. TECHNIQUES OF S O L U B I L I Z A T I O N OF DRUGS,
edited by Samuel H. Yalkowsky
SECOND EDITION,
REVISED AND EXPANDED
Edited by
M A R C E L
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iv
Preface to the Second Edition I v
Joseph R. Robinson
Vincent H. L. Lee
Preface to the First Edition
VII
viii / Preface to the First Edition
the time course and specificity of drugs in the body; these have been
identified by various names, such as "prodrug," "controlled release,"
"sustained release," "prolonged release," and "timed release." In each
of these types of drug delivery there has been some degree of con-
trol over the temporal pattern of drug placement in the target tissue.
However, a maximization of therapy has generally not been achieved.
To maximize drug utilization, it is necessary to deliver drug to the
target tissue in the correct amount at the proper time to elicit the
desired response. Moreover, drug delivery must be continued at a
rate such that the condition in question is cured or controlled in a
minimum time with the fewest side effects. Thus, an appropriate
definition of controlled drug release is as follows: It is the phasing
of drug administration to the needs of the condition at hand so that
an optimal amount of drug is used to cure or control the condition
in a minimum time. In some situations this might mean that drug is
delivered more promptly for short periods of time and in other cases
it would mean prolongation of drug levels. In the latter category
we employ the terms "sustained release" and "prolonged release"
interchangeably; this designates only one aspect of controlled release,
namely, to produce protracted levels of drug in the body. Actually,
controlled drug delivery is the desired effect of all drug delivery
systems, and all presently fabricated sustained and prolonged drug
delivery systems provide some degree of control, albeit incomplete.
Thus, whereas second-generation sustained release products have
made significant advances over their first-generation counterparts,
none of the commercially available systems presently on the market
is in truth a controlled drug delivery system; some are just better
than others.
The present text was designed to fulfill a perceived need to pro-
vide a comprehensive picture of the sustained release drug product
area. Admittedly, there are numerous review articles, chapters, and
a few texts devoted to one or more topics in the sustained release
drug or chemical area, but a current and comprehensive treatment
appears to be lacking.
To accomplish this task, I have organized the book in the follow-
ing manner. The principal chapters describing the various physical,
chemical, and bioengineering approaches to the preparation of sus-
tained release drug products are Chapters 3, 4, 6, and 7. The
various physiological, drug-related, and formulation constraints on
the design of these products are described in Chapters 1 and 2,
the early part of Chapter 3, and Chapter 5. Chapters 1, 2, and
3 focus primarily on the physiological and drug-related constraints,
and Chapter 5 deals with parenteral drug and formulation biocom-
patibility considerations. Thus, the first seven chapters provide a
description of the problems and potential approaches of sustained
release drug product preparation. I have elected to place those
Preface to the First Edition I ix
Joseph R. Robinson
Contents
Part I
FUNDAMENTALS OF C O N T R O L L E D RELEASE
DRUG DELIVERY
I. Introduction
II. Terminology
III. Rationale of .Sustained/Controlled D r u g Delivery
IV. Factors Influencing the Design and Performance
of Sustained/Controlled Release P r o d u c t s
xii I Contents
V. Physicochemical P r o p e r t i e s of a D r u g Influencing
Design and Performance 12
VI. Biological Factors Influencing Design and
Performance of S u s t a i n e d / C o n t r o l l e d Release
Products 15
VII. Selected Routes of D r u g Administration 36
VIII. Drug Targeting 56
IX. Conclusions 59
References 61
2. Theory of Mass T r a n s f e r 95
Ronald R. Burnette
I. Introduction 96
II. Random Walk I n t e r p r e t a t i o n of Diffusion 96
III. Fick's First and Second Law 97
IV. Passive Diffusion T h r o u g h a Membrane—The
Partition Coefficient 113
V. Passive Diffusion T h r o u g h a Membrane—The
Stagnant Diffusion Layer 119
VI. Application of Fick's Second Law to t h e
Determination of t h e N o n - S t e a d y - S t a t e
Output Flux T h r o u g h the Skin 127
VII. Application of Fick's First Law to the
Determination of D r u g Release from a
Polymeric Matrix or Ointment 130
VIII. Diffusion with Simultaneous Reaction 135
IX. Additional Concerns in Diffusional Mass
Transport 135
References 136
Jorge Heller
I. Introduction 140
II. Polymer Classification and Polymerization
Mechanisms 141
III. Polymerization Methods 152
IV. Polymer Fabrication 156
V. Polymer P r o p e r t i e s 164
VI. Polymer Characterization 169
Contents I xiii
Jorge Heller
I. Introduction 213
II. Review of General Principles 219
III. Summary 240
References 241
I. Introduction 254
II. A d v a n t a g e s of Controlled Release Dosage Forms 255
III. Disadvantages of Controlled Release Dosage
Forms 257
IV. Compounds That Are Unsuitable for Controlled
Release 259
V. In Vitro Considerations 262
VI. In Vivo Considerations 263
VII. Bioavailability T e s t i n g 284
VIII. Conclusions 288
References 289
I. Introduction 294
II. Terminology 294
III. Rationale for Controlled Release Dosage Forms 296
xiv I Contents
Part II
DESIGN AND F A B R I C A T I O N OF TECHNOLOGY BASED
C O N T R O L L E D RELEASE DRUG DELIVERY SYSTEMS
I. Introduction 337
II. Prodrugs 339
III. Classical P r o d r u g s as Chemical Delivery
Systems 340
IV. Sustained Chemical Delivery Systems 342
V. Sustained Delivery of Natural Soft Drugs 343
VI. Brain-Specific Sustained Chemical Delivery
Systems 357
VII. Conclusions 368
References 369
I. Introduction 373
II. Design and Fabrication of Oral Systems 375
III. Summary 420
References 421
Contents I xv
I. Introduction 434
II. Major Routes of P a r e n t e r a l Administration 435
III. Biopharmaceutics of Sustained /Controlled
Release P a r e n t e r a l D r u g P r o d u c t s 437
IV. Biocompatibility of Polymeric Material 440
V. S u s t a i n e d / C o n t r o l l e d P a r e n t e r a l Dosage Forms 442
VI. Summary 464
References 465
Yie W. Chien
I. Introduction 482
II. Historical Development 482
III. Approaches to Development of Implantable
T h e r a p e u t i c Systems 484
IV. Benefits of Controlled D r u g Administration
Via Implantation 509
V. Medical Aspects of Implantation 512
References 516
Yie W. Chien
I. Introduction 524
II. Skin as a Site for D r u g Infusion 524
III. Fundamentals of Skin Permeation 528
IV. Approaches to Development of T r a n s d e r m a l
T h e r a p e u t i c Systems 532
V. Kinetic Evaluation of T r a n s d e r m a l T h e r a p e u t i c
Systems 538
VI. Formulation Design and Optimization 547
References 549
xv i I Contents
Part I I I
B I O C H E M I C A L AND MOLECULAR BIOLOGY APPROACHES
TO C O N T R O L L E D DRUG DELIVERY
Rudy L. Juliano
I. Introduction 556
II. P r e p a r a t i o n of D r u g Containing Microparticulates 557
III. In Vivo B a r r i e r s to Microparticulate Distribution 561
IV. Selected Examples of D r u g Delivery with
Microparticulate C a r r i e r s 566
V. Summary 571
References 572
Ruth Duncan
I. Introduction 582
II. Mechanisms for Achieving Selective C a p t u r e 596
III. Use of Selective Endocytosis for D r u g
Targeting 604
IV. Conclusions 606
References 607
I. Introduction 624
II. Tumor Antigens Defined by Monoclonal
Antibodies 624
III. D r u g - A n t i b o d y Conjugates 633
IV. Conclusions 641
References 642
Ronald R. B u r n e t t e , P h . D . , P h a r m . D . , M . S . School of P h a r m a c y ,
University of Wisconsin, Madison, Wisconsin
xvh
xviii I Contributors
I. Introduction 4
II. Terminology 5
III. Rationale of S u s t a i n e d / C o n t r o l l e d D r u g Delivery 7
IV. F a c t o r s Influencing t h e Design and Performance of
S u s t a i n e d / C o n t r o l l e d Release P r o d u c t s 9
V. Physicochemical P r o p e r t i e s of a D r u g Influencing
Design and Performance 12
A. Aqueous Solubility 13
B. Partition Coefficient and Molecular Size 14
C. D r u g Stability 14
D. Protein B i n d i n g 15
VI. Biological Factors Influencing Design and Performance
of S u s t a i n e d / C o n t r o l l e d Release P r o d u c t s 15
A. Absorption 16
B. Distribution 18
C. Metabolism 23
D. Duration of Action 26
E. Side Effects 30
F. Margin of Safety 31
3
4 / Li et al.
I. INTRODUCTION
II. TERMINOLOGY
.SUSTAINED RELEASE
TIME
III. R A T I O N A L E OF S U S T A I N E D / C O N T R O L L E D
DRUG DELIVERY
The basic rationale for controlled drug delivery is to alter the phar-
macokinetics and pharmacodynamics of pharmacologically active moieties
by using novel drug delivery systems or by modifying the molecular
structure and/or physiological parameters inherent in a selected route
of administration. It is desirable that the duration of drug action
become more a design property of a rate-controlled dosage form, and
less, or not at all, a property of the drug molecule's inherent kinetic
properties. Thus, optimal design of controlled release systems
8 I Li et al.
where t^/2 is the half-life. Since the therapeutic index for most
drugs is around 2, it will be necessary to dose the patients at inter-
vals shorter than the half-life. Such inconvenient regimens often
result in reduced compliance and inadequate treatment. For drugs
with pronounced multicomp art mental characteristics, a better estimate
of the dosing interval may be obtained by replacing t i / 2 with 0.693*
(MRT), where MRT is the mean residence time. In such cases, the
drug must be given even more frequently than suggested by Eq. (1).
In general, the dosing interval may be increased either by modi-
fying the drug molecule to decrease the rate of elimination (k e j) or
by modifying the release rate of a dosage form to decrease the rate
of absorption ( k a ) . Both approaches seek to decrease fluctuations
in plasma levels during multiple dosing, allowing the dosing interval
to increase without either overdosing or underdosing. When attempt-
ing to extend the dosing interval by decreasing the rate of absorp-
tion, the formulator will be confronted with the physiological con-
straint of a finite residence time at the absorption site. For example,
an effective absorption time for orally administered drugs is about
9-12 h r . If the rate of absorption decreases too much, some of the
unabsorbed drug will pass into the large intestine, where absorption
is slower and more variable and where bacterial degradation of the
drug may occur. Thus, drugs with half-lives of 6 hr or less and
Influence of Drug Properties on Design I 9
Therapeutic serum
Drug concentrations a Terminal
substance (C* . to C* ) half-lives 0
min max
Digit oxin 14-30 yg/liter 6.3-11.3 days
Digoxin 0.9-2 yg/liter 1.4-2.2 days
Lidocaine 1.5-5 mg/liter 1.2-1.7 hr
Lithium 0.5-1.3 mEq 14.2-24.1 hr
Nortriptyline 50-140 yg/liter 18.2-35.0 hr
Phenytoin 10-20 mg/liter 18.7-27.6 hr
Procainamide 4-8 mg/liter 2.5-4.7 hr
Propranolol 20-50 yg/liter 1.1-9.9 hr
Quinidine 2-5 mg/liter 3.0-16.0 h r
Salicylates 150-300 mg/liter 2.9-22 hr
Theophylline 10-20 mg/liter 5.3-8.3 h r
Scheme 1
from the dosage form as the rate-limiting step instead. Thus, drug
availability is controlled by the kinetics of drug release rather than
12 I Li et al.
Drug release
(Drug)^ „ • (Drug)™ . *- Elimination
to &
Dosage form Target area
Scheme 2
A. Aqueous Solubility
C. D r u g Stability
The stability of a drug in the environment to which it is exposed is
another physicochemical factor to be considered in the design of sus-
tained/controlled release systems. Drugs that are unstable in the
stomach can be placed in a slowly soluble form or have their release
delayed until they reach the small intestine. However, such a strate-
gy would be detrimental for drugs that either are unstable in the
small intestine or undergo extensive gut-wall metabolism, as evidenced
Influence of Drug Properties on Design I 15
D. Protein Binding
It is well known that many drugs bind to plasma proteins with a con-
comitant influence on the duration of drug action [44-48]. Since
blood proteins are for the most part recirculated and not eliminated,
drug protein binding can serve as a depot for drug producing a pro-
longed release profile, especially if a high degree of drug-binding
occurs. This aspect of prolonged drug activity has been described
in the literature [49]. There are, however, other drug-protein in-
teractions that have a bearing on drug performance. Levine [50] has
shown that quaternary ammonium compounds bind to mucin in the GI
tract. Drugs bound to mucin may increase absorption, if the bound
drug act as a depot. However, if degradation and/or washing of the
drug further down the GI tract occurs, binding of drug to mucin may
result in a reduction of free drug available for absorption. The issue
of drug and vehicle interaction with the mucin layer and its influence
on extent and duration of drug absorption has been reviewed [51] .
A. Absorption
B. Distribution
S = [(k
V 12+k21)/k21]Vp (2)
T/P = k 1 2 / ( k 2 1 - 3) (5)
Vdss
Drug T/P (liters) Ref.
Amoxicillin 1.04 22 91
Cefazolin 2.20 9 92
Diazepam 2.85 130 93
Digoxin 4.31 500 94
Furosemide 0.96 5 95
Meperidine 2.04 289 96
Metolazone 2.71 113 97
Pentobarbital 1.30 63 98
Pivampicillin 1.16 13 99
Procainamide 14.35 62 100
Sulfisoxazole 0.60 11 101
Theophylline 0.97 40 102
Tobramycin 1.78 34 103,104
Tolbutamide 0.27 24 105
Trimethoprim 1.24 12 106
V s '1/2,6 TBCb
Drug (liters) (hr) (ml/min) Ref.
Terminal l o n g - l i n e a r half-life.
b
T o t a l body clearance = V d s s (0.693/t ).
C. Metabolism
Metabolism of a drug can either inactivate an active drug or convert
an inactive drug to an active metabolite. Metabolic alteration of a
drug can occur in a variety of tissues, some of which are richer in
enzymes than others. For example, the organ most responsible for
metabolism is the liver and thus the greatest metabolic conversion
occurs after a drug has been absorbed into the general circulation.
Clearly, for optimal bioavailability, the route of drug administration
may be dictated by the drug's metabolic pattern.
Metabolism of a drug will be reflected in the elimination constant
of a drug or by the appearance of metabolite. It is possible to in-
corporate this pharmacokinetic property into the design of a con-
trolled release product, provided that the rate and extent of meta-
bolism are predictable and that the rate constant(s) for the process
are not too large. Undoubtedly, complex metabolic patterns would
make the design much more difficult, particularly when biological
activity is wholely or partly due to a metabolite, as is the case in
24 I Li et al.
A v e r a g e T / P ratio i s 1.
^ A v e r a g e total body clearance at s t e a d y s t a t e is about 80 ml/min.
c
A s s u m e t h a t elimination of d r u g o c c u r s primarily in t h e central com-
partment.
D. Duration of Action
h/2
(hr) Td = 6 h r Td = 8 h r Td = 12 h r
($ /$.)max
m 1
5 199 99 49
10 99 49 24
25 99 19 9
50 19 9 4
75 12.3 5.7 2.3
100 9 4 1.5
125 7 3 1
250 3 1 0
325 2 0.5 -
500 1 - -
1000 - - -
Half-life
Drug (min) Ref.
Half-life Duration
Drug (hr) (hr) Ref.
Bishydroxycoumarin 27 h r 151
Chlordiazepoxide 15 h r 152
Chlorphentermine 41 h r 153
Chlorpropamide 36 h r 154,155
Diazepam 54 h r 156
20 h r 157
Ethchlorvynol 24 h r 158
Digitoxin 5-7 d a y s 159
28 d a y s 160
Digoxin 34 h r 159,161
Guanethidine 9-10 d a y s 162
Meprobamate 11.3 h r 163
Phenytoin 22 h r 164
Warfarin 52 h r 165
E. Side Effects
F. Margin of Safety
Among the indices used to describe the margin of safety of a drug
[188-190], the therapeutic index as defined in Eq. (7) is the most
widely used:
32 I Li et al.
Therapeutic
Drug index Ref.
Range of therapeutic
Drug concentration
studies not only reduced the incidence and severity of angina attacks
but also lowered the nitroglycerin requirements. Kamil and Klinger
[206] as well as Feinblatt and Ferguson [207] reported similar find-
ings with pentaerythritol tetranitrate, another drug used in angina
pectoris. The conflicting nature of the above reports suggests that
additional studies are warranted to establish the role of sustained
release preparations as a prophylactic aid in angina pectoris. Per-
haps the acute and fleeting nature of angina attacks [205] , the large
placebo effect [205], and the development of tolerance with chronic
administration of long-acting oral nitrate preparations [208] should
be major consideration in the design and interpretation of such stud-
ies. An interesting statement on the need for prolonged action forms
of nitrates in the prophylactic treatment of angina pectoris was made
by Wilson [209]. He noted that prophylaxis carries with it the dan-
ger of obscuring the warning symptoms of pain, eventually leading
to over-exertion with potentially harmful results.
of Jarrett and Keen [220], Hayner et al. [221], Freinkel et al. [222],
and Faiman and Morrhouse [223] obtained results opposite to those of
the former investigators, that is, a diurnal variation in blood glucose
existed in the diabetic but not in the normal subject, with blood glu-
cose levels significantly higher in the morning than in the afternoon.
Freinkel et al. [222] also found that, in normal subjects, insulin level
was higher in the morning than in the afternoon. Rigas et al. [224]
postulated that insulin synthesis and storage proceeded to a greater
extent during the night than during the day, thus accounting for
Freinkel's observations on diurnal variation in insulin levels. Theo-
retically, once diurnal variations in blood glucose and/or insulin are
established, controlled release oral hypoglycemic products could be
designed to release their contents in accordance with circadian rhythm.
However, the fluctuation in blood glucose levels in diabetics is not
controlled solely by diurnal variations but also by such variables as
diet and exercise [225], Conceivably, the net result of interaction
of these two influences is to diminish the importance of circadian
rhythm in dosage form design.
Perhaps the classes of drugs that would benefit the most from in-
corporation of circadian rhythm into their dosing regimen are the
chemotherapeutic agents and peptide hormones. That the timing of
chemotherapy is possible in conferring greater specificity is based on
the assumption that, unlike malignant tissues, normal tissues are un-
der more stringent circadian control. Hrushesky [226] demonstrated
that during the course of treatment of ovarian cancer patients with
a combination of adriamycin and cisplatin, administration of adriamycin
in the morning and cisplatin in the evening caused fewer complications
than a regimen in which the order of dosing of these drugs was re-
versed. The secretion of neuropeptides and peptide hormones like
LHRH, parathyroid hormone, and growth hormone is also under cir-
cadian control [227]. Thus, the treatment of conditions by a number
of these substances, notably LHRH [228-230], parathyroid hormone
[231], and triiodothyronine [232] has been found to benefit more
from intermittent, periodic administration than from constant infusion,
in part because a constant tissue level of these substances may lead
to down regulation of their receptors [233-237] . The net effect of
circadian regulation of these substances is to make the design of a
controlled release system for such substances more challenging, as
exemplified by a prototype delivery device programmed to release
melatonin, a pineal gland hormone, in a periodic fashion [238].
delivery system design, the parenteral and oral routes have received
by far the most attention, although transdermal route is gaining at-
tention recently. At the same time, advances in biotechnology have
made possible an increasing number of peptides and proteins which,
by virtue of the biophysical and biochemical properties, have made
specific demands on the route of delivery as well as on the design of
delivery systems. Thus, routes which were of minor importance as
ports of drug delivery in the past have assumed added importance in
peptide and protein delivery. These include the buccal, rectal, nasal,
pulmonary, vaginal, intrauterinal, and ocular routes. The purpose
of this section is to present an overview of the physiological con-
straints inherent in each of the routes mentioned above.
A. Parenteral
Strictly speaking, parenteral products are all systems administered
outside of the GI tract. However, parenteral routes are more common-
ly restricted to injectables such as subcutaneous, intramuscular, intra-
peritoneal, intrathecal, and intraventricular sites.
1. Intravenous /Intraarterial
The intravenous route is attractive because drugs are placed directly
into the blood with the associated potential to give an immediate bio-
logical response. However, sustaining blood concentrations of drugs
given by intravenous injection poses a considerably challenge. Al-
though continuous intravenous infusion can be tailored to maintain
a constant and sustained drug level within a therapeutic concentration
range during the entire treatment period, such a mode of drug ad-
ministration necessitates continuous hospitalization during treatment
and requires frequent drug level monitoring.
There are several reasons for the lack of commercial sustained
release intravenous products. Aside from the irretrievable nature of
such injected drugs, there are the issues of biocompatibility and
limitations on the size of injected drugs. Thus, wishing to avoid
blockage of small capillaries requires that only very small particles
be employed as physical systems for intravenous injections. However,
the reticuloendothelial system, consisting primarily of liver, spleen,
lung, and bone marrow, sequesters "foreign" substances out of the
blood stream rapidly, thus making it difficult to sustain drugs via
this route.
Numerous attempts to provide either prolongation of drug release
or spatial placement of drug, a very desirable attribute for cancer
chemotherapy, have been made. Each appears to suffer from one or
more deficiencies. Thus, loaded red blood cells, where a drug is
38 I Li et a/.
2. Intramuscular /Subcutaneous
Next to oral administration, injection into subcutaneous or muscular
tissues is the most commonly used and acceptable route of drug ad-
ministration. These routes of administration are most useful either
when the disease state or the pharmacokinetic properties of a drug
preclude oral dosing, or prolonged drug action is desired. The
latter can be achieved in a number of ways [241,248], including re-
duction of aqueous solubility, gelling of the oily vehicle, use of bio-
degradable systems, implants, or a combination of these. All of these
approaches aim to decrease the release rate of a drug from its dosage
form and will be discussed further in Chapter 10. A major factor
that needs to be considered during development of biodegradable sys-
tems and implants is biocompatibility of the polymers. Release rate
from implants may decrease with time when a fibrous envelope is
Influence of Drug Properties on Design I 39
B. Oral
The oral route is by far the most popular route of drug administra-
tion. Nevertheless, current knowledge on mechanisms of drug ab-
sorption, GI transit and the microenvironment of the GI tract is still
incomplete. In addition, oral administration is also beset with inher-
ent physiological constraints such as chemical degradation in the
stomach, gastric empyting, intestinal motility, mucosal surface area,
specific absorption sites, and metabolic degradation during passage
through the mucosa and subsequently the liver. Adding to these
constraints is the commonly substantial intra- and intersubject vari-
ability associated with some of these factors. Generally, these factors
cannot be controlled and hence severely limit the design of oral drug
delivery systems.
The duration of a drug after oral administration is mainly a func-
tion of drug-releated properties such as rate of absorption and clear-
ance as well as residence time of the delivery system at the absorp-
tion site. Most sustained release drug delivery systems developed
thus far are aimed at slowing the apparent absorption rate by reduc-
ing drug release rate from the dosage form. However, these systems
will have only limited utility in oral controlled administration of drugs
unless they can remain in the vicinity of the absorption site for the
life time of drug delivery.
The residence time of most sustained/controlled release dosage
forms is primarily determined by gastric emptying and intestinal
motility. Gastric emptying is influenced by factors such as auto-
nomic and hormonal activity, and volume, composition, viscosity,
osmolality, pH, caloric value, temperature of stomach contents as
well as by many drugs [271]. The human/canine stomach behaves
differently in the fed and fasted states [272]. During the fed state,
fluids and solid particles smaller than 2 mm are discharged together
whereas solid particles larger than 2 mm, including pellets and tablets
are retained until arrival of the next phase III of the migrating motor
Influence of Drug Properties on Design I 47
C. Buccal /Sublingual
Drugs can be absorbed from the oral cavity through the oral mucosa
either sublingually (under the tongue) or buccally (between the cheek
and gingiva). In general, rapid absorption from these routes is ob-
served because of the thin mucous membrane and rich blood supply.
For highly hydrophilic drugs (log P < 2), which also suffer from ex-
tensive presystemic elimination and require a rapid onset of action,
sublingual or buccal administration may offer advantages over oral
administration. After absorption, drug is transported through the
deep lingual vein or facial vein which then drains into the general
circulation via the jugular vein. Thus, the buccal and sublingual
routes can be used to bypass hepatic T,first-passTT elimination. Lym-
phatic uptake of drug also occurs, but is less common [280].
Drug absorption into the oral mucosa is mainly via passive dif-
fusion into the lipoidal membrane [281-283]. Compounds with favorable
oil-to-water partition coefficients are readily absorbed through the
oral mucosa. Since the mean pH of saliva is 6.0, adequate absorp-
tion through the oral mucosa occurs if the pK a is greater than 2 for
an acid or less than 10 for a base. An oil-water partition coefficient
range of 40-2000 is considered optimal for drugs to be absorbed
sublingually [284,285]. Compounds administered by either the buccal
Influence of Drug Properties on Design I 43
D. Rectal
E. Nasal
For many years, the nasal route was used primarily for local action
on the nasal mucosa. Despite its use in systemic delivery of desmo-
pressin and vasopressin, its use as an alternate route for poorly ab-
sorbed oral drugs seems to have been ignored until recently. A
variety of drugs including propranolol [310] , testosterone [311] ,
naloxone [312], buprenorphrine [312], ergotamine tartrate [313],
clofilium tosylate [314], cromolyn sodium [315], meclizine [316], as
well as endogenous hormones such as luteinizing-hormone-releasing
hormone [317], tetracosactrin [318], oxytocin [319], ACTH [320],
insulin [321-324], and enkephalins [325], have been shown to be
absorbed nasally in animals and humans. By virtue of relatively
rapid drug absorption, possible bypassing of presystemic clearance,
and relative ease of administration, delivery of drugs by the nasal
route offers an attractive alternative for administering systemically
active drugs.
The anatomy of the nasal cavity is described in detail elsewhere
[326,327]. The thickness and vascularity of the mucous membrane
Influence of Drug Properties on Design I 45
F. Pulmonary
Delivery of medication to the respiratory tract for localized therapy
of respiratory diseases is commonly accomplished via the airways be-
cause of their enormous surface area and accessibility [330] . The
respiratory tract consists of a nasopharyngeal region, a tracheo-
bronchial region, and lungs (bronchioles and alveoli). The diameter
of the dichotomous branchings of the bronchial tree decreases in the
distal parts of the respiratory tract, with a simultaneous increase in
total cross-sectional area and the total surface area [331]. Thus,
the flow in the central airway is rapid and turbulent, whereas flow
in the peripheral airways is smooth and laminar [332] . The total sur-
face area of alveoli in an adult is about 35 m2 during expiration and
about 100 m2 during deep inspiration [333] . Thus, most solute ex-
change takes place at the alveolar level.
For purposes of discussion of the deposition and clearance of
inhaled aerosols, the airways can be divided into three functional
regions [334] (Fig. 2):
Naso pharyngeal:
particles greater Pharynx
than 5^im deposited
Larynx
Tracheo bronchial1
particles between Trachea
2 and 5 ^m deposited Primary bronchi
in this region Secondary bronchi
Pulmonary: Terminal bronchioles
particles less than
2>um deposited by Respiratory
bronchioles
diffusion and random Alveolar duct
capture.
Alveoli
100 r-
Alveolar and
terminal airway
^ 801— deposition
/ Mouth breathing
iZ 60
o
Q.
Q 40
20
2 '•/. ••"
/
0 1 2 4 6 8 10
%
Submicron
range PARTICLE DIAMETER (/xm)
Nasal
l . Mouth breathing
Oral
f
— / \
Mucociliary escalator L^— Pharyngeal
7 0 % deposition ^"v
(10-30/im)
L
astrointestinal tract
Tracheobronchial Blood
Urn—
6 % deposition (depending on
(10/im) solubility)
J
Lower airways 8 lungs
2 4 % deposition
(5/im -lower airways) Lymph
nodes
(< 1 /Am -alveolar
1 ^ parenchyma) Peribronchial
and
subpleural
lymphatic
T Macrophages •-Interstitial
H
channels
space
EXCRETION
Residue
G. Vaginal
Intravaginal controlled release drug administration of steroidal com-
pounds or spermicidal agents is aimed at obtaining contraception for
50 1 Li et al.
and that the vagina can accomodate foreign bodies of reasonable size
with minimal discofort for an extended period of time. There are
two common types of vaginal rings: homogeneous [380] and shell [385].
Burst effect of drug release on insertion and a declining release rate
after extended wear are commonly observed with homogenous rings.
Shell rings apparently minimize the burst effect and are able to main-
tain a steady drug release rate. For most vaginal rings, the rate of
vaginal drug absorption shortly after insertion is controlled by either
an aqueous hydrodynamic diffusion layer or by the vaginal wall. At
later times, the rate of vaginal absorption is determined by the drug
release rate from the ring [392].
Reported problems associated with the use of vaginal rings are:
erosion of the vaginal wall, ring expulsion, interference with coitus,
unpleasant ring odor, and difficulty with storage and sanitation [393],
These problems are usually the major causes for discontinued use of
vaginal rings and, because of these problems, vaginal rings have re-
ceived only moderate acceptance.
A potential intravaginal contraceptive system free of most of the
aforementioned problems is the biodegradable microsphere. The ratio-
nale for its development is that inert particles have been demonstrated
to be able to migrate from the vagina across the cervix into the fallopi-
an tube or the perimetrial lining of the uterus without causing erosion
of the vaginal wall by virtue of its small size [294,295] .
Microspheres for intracervical administration have also received
attention. Small doses of progesterone can be released locally to alter
the structure of the cervical mucus so as to interfere with sperm
migration [396] . In addition, a medicated intracervical system has
been tested [397] . The rationale for its development is that contrac-
tility is less severe in the lower segment of the uterus, especially the
cervix. This system still incurs the problems of expulsion and pos-
sibility of infection and does not offer enough advantages over exist-
ing intravaginal or intrauterinal systems to be worth pursuing.
H. Intrauterine
The effectiveness of nonmedicated intrauterine devices (IUDs) is pri-
marily dependent on the relationship of the device morphology (size,
shape, and area) to uterine geometry [398]. The human uterus is a
pear-shaped, muscular structure, about 3 in. in length and about 2
in. wide, consisting of a body, fundus, isthmus, and cervix. Its
wall has three layers: an external peritoneal layer (perimetrium) , a
middle muscular layer (myometrium), and an inner mucous membrane
(endometrium). This organ undergoes dynamic changes in the size
and shape of its various segments during different phases of the
menstrual cycle [399]. Lack of structural adaptability and unfavor-
able geometry of the device may lead to clinical complications such
52 / Li et ah
I. Transdermal
The skin is one of the most extensive and readily accessible organs
of the human body. It covers an area of about 2 m2 and at any
point in time is in contact with about one-third of all blood circulating
through the body [407]. Skin consists of three tissue layers: epi-
dermis, dermis, and hypodermis (subcutaneous tissue). The rate-
limiting step in percutaneous absorption of most drugs appears to be
passage through the stratum corneum [408-414] . The pathway of
drug movement through this layer is believed to be mainly transcellu-
lar, although the paracellular pathway may become important for small
molecular weight compounds [408] . In addition to being a diffusion
barrier, the stratum corneum also serves as a reservoir for compounds
such as corticosteroids, griseofulvin and many other drugs. While
drugs are carried away by the capillary network upon reaching the
subcutaneous tissue, there is evidence that certain drugs such as
thyroxin, 3-methoxypsoralen, estradiol and corticosteroids, remain
in this layer for an extended period of time [415-417]. Such locali-
zation of drugs may prove desirable for exerting local effects in deep-
er tissues of the skin or for prolonged release of drugs.
In the past, topically applied dermatological drugs were used for
localized treatment of skin diseases only. Recently, due to a better
understanding of the anatomy and physiology of the skin as well as
a more thorough understanding of percutaneous absorption, the limited
permeability of human skin has also been utilized for systemic drug
administration.
There are several advantages to the transdermal route provided
the drug is absorbed in sufficient quantity to exert a systemic effect.
Thus, it is possible to:
J. Ocular
For treatment of many disease affecting the external eye and anterior
segment of the eye, topical instillation is preferred over systemic ad-
ministration because a high drug concentration at the absorbing mem-
brane can be obtained, thereby maximizing drug delivery to the af-
fected tissues while minimizing systemic side effects. However, topi-
cal application of drugs to the eye is impeded significantly by effici-
ent ocular physiological protective mechanisms, such as drainage, tear
turnover, limited permeability of corneal membranes to most drugs,
and aqueous humor turnover. Typically, drug from an instilled aque-
ous solution is essentially eliminated from the precorneal area within
1-2 min of application [435] , so that less than 3% of an applied dose
penetrates into the aqueous humor following topical instillation of an
aqueous solution [436]. The duration of drug action is, therefore,
brief, and frequent dosing is needed.
The duration of drug action in the eye can be extended by two
approaches: (a) reducing drainage through the use of viscosity-
enhancing agents, suspensions, emulsions, ointments, erodible and
nonerodible matrices [437] and (b) improving corneal drug penetration
through the use of ionophores [438], ion-pairs [439], liposomes [440],
and prodrugs [441]. For low viscosity solutions, the improvement
in ocular bioavailability is usually modest [442-444]. Suspensions
and emulsions suffer from the same problem as low viscosity solutions
in that the contact time, though lengthened, is still relatively brief.
Moreover, in the case of suspensions, the solid particles must dissolve
slow enough to offer an advantage over a saturated solution [455].
The release rate of drug is usually rapid from swollen hydrophilic
matrices such as soft contact lenses. Release rate from lipophilic
ointments can be slower, but these systems suffer from the problem
of blurring vision thus reducing their use to night time medication.
The use of ion-pair and ionophores is limited to a small group of drugs
and their improvement is still considered moderate [438,439]. Lipo-
somes appear to be able to enhance the absorption of large, hydro-
philic molecules [446-450] and may prove to be useful in delivering
macromolecules such as peptides and proteins. Their usefulness in
delivering lipophilic molecules seems to depend on the way the drugs
are incorporated into the liposomes [446,447,450] . The use of lipo-
somes in ocular drug delivery has been reviewed [440].
Prodrugs can be used to improve ocular bioavailability by enhanc-
ing corneal penetration, protecting the parent compound from meta-
bolism, or decreasing its elimination. Recently, the first ophthalmic
prodrug, dipivalyl epinephrine, was marketed under the trade name
Propine-^. With improved corneal penetration characteristics, a much
lower dose of epinephrine is needed, thereby reducing side-effects.
Via a different mechanism to affect ocular drug absorption, systems
56 I Li et al.
PASSIVE TARGETING
H | capillary
tsieve plate blockage
passage
normal
ACTIVE TARGETING capillary
diameter
I—antibody-antigen events H
h-extracorporeal guidance H
OOI I lymphotropism 1 4 7 10 100
01 I 4
MICROSPHERE
TARGET
IX. CONCLUSIONS
In the past decade, the number of new drug entities appearing on the
market yearly has declined and pharmaceutical manufacturers for a
variety of reasons have a renewed interest in improving existing
dosage forms and developing more sophisticated drug delivery systems,
including those employing the principles of sustained/controlled drug
release. The need for a sustained/controlled release preparation often
arises: (a) as a result of undesirable drug properties, such as short
biological half-life, local irritation, extensive metabolism, and narrow
therapeutic index, (b) perhaps through the nature of the disease
state, or (c) for patient compliance reasons. Most important of all
is the need to improve the efficacy and safety of drug through proper
temporal and/or spatial control of drug release.
In considering a drug for this mode of drug delivery, certain
criteria have to be examined and evaluated. These are the physico-
chemical, pharmacokinetic and pharmacodynamic characteristics of the
drug. With each drug property there is a range of values that lends
itself to the design of sustained/controlled release products, and
outside this range the design becomes more difficult or, in the extreme,
prohibitive. Extremes of aqueous solubility, oil /water partition coef-
ficients, binding, extensive metabolism/degradation of the drug dur-
ing transit from the point of drug delivery to the target area, and
60 I Li et ol,
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I . INTRODUCTION
I I . TERMINOLOGY
only the dose (D) and dosing interval (T ) can vary and,
for each
Drug
substance
Digit oxin
Digoxin
Lidocaine
Lithium
Nortriptyline
Phenytoin
Procainamide
Propranolol
Quinidine
Salicylates
pharmacological studies.
A. Aqueous Solubility
Since drugs must be in solution before they can be
absorbed, com
carriers readily.
al. [41] have shown that, for many body tissues, such as
the gas
C. Drug Stability
approaches.
D. Protein Binding
blood proteins are for the most part recirculated and not
eliminated,
A . Absorption
ster [71], Callender [72], and Bent ley and Jacobs [73]
detected no
B. Distribution
Ratio
Drug
Amoxicillin
Cefazolin
Diazepam
Digoxin
Furosemide
Meperidine
Metolazone
Pentobarbital
Pivampicillin
Procainamide
Sulfisoxazole
Theophylline
Tobramycin
Tolbutamide
peutic range, one can probably assume that such drugs are
inherently
Chlorphentermine
Clindamycin
Diazepam
Digoxin
Lidocain
Meperidine
Metolazone
Ouabain
Pentobarbi ta l
Phenytoin
Practolol
Procainamide
Propranolol
Quinidine
C. Metabolism
pa r tmen t .
predictable.
D. Duration of Action
h/2
(h r )
Di (mg) 5
10
25
50
75
100
125
250
325
500
D r u g
Ampicillin
Cephalexin
Cloxacillin
Furosemide
Levodopa
Penicillin G
cor t icos tero ids tha t forms the bas i s for a l t e rna
te -day dosing schedule
Drug (h r ) (h r ) Ref.
Half-Lives
D r u g
Bishydroxycoumarin
Chlordiazepoxide
Chlorphentermine
Chlorpropamide
Diazepam
Ethchlorvynol
Digitoxin
Digoxin
Guanethidine
Meprobamate
Phenytoin
Warfarin Half-life 27 h r 15 h r 41 h r 36 h r 54 h r
20 h r 24 h r 5-7 days 28 days 34 h r 9-10 days 11.3
h r 22 h r 52 h r Ref. 151 152 153 154,155 156 157
158 159 160 159,161 162 163 164 165
E. Side Effects
can induce local and systemic side effects which can often
be circum
F. Margin of Safety
cosides and ant iar rhythmic (Table 11) [26 ,113] . In des
igning controlled or sus ta ined release systems for d rugs
Drugs
D r u g
Aprobarbi ta l
Digitoxin
Diphenhydramine
Penicillin
Phenobarbi tal
Drug concentration
A. Parenteral
1. Intravenous /Intraarterial
B. Oral
ing drug release rate from the dosage form. However, these
systems
monly observed for volumes of fluid less than 100 ml. The
onset of
C . Buccal /Sublingual
Drugs can be absorbed from the oral cavity through the oral
mucosa
For highly hydrophilic drugs (log P < 2), which also suffer
from ex
deep lingual vein or facial vein which then drains into the
general
D. Rectal
the rectum does not have any active motility. Normally the
rectum
region of the rectal wall. The upper veins drain into the
portal cir
E. Nasal
For many years, the nasal route was used primarily for
local action
the nasal mucosa may affect the rate and extent of drug
absorption.
F. Pulmonary
Naso pharyngeal:
particles greater
Tracheo bronchial 1
particles between
2 and 5 ^m deposited
in this region
Pulmonary:
2>um deposited by
capture.
t ree .
^ 801— deposition
iZ 60
Q 4 0
1 ^ L^— L Urn—
systemic effects.
G. Vaginal
H. Intrauterine
52 / Li et ah
I. Transdermal
ment is that the drug delivery system rather than the skin
acts as
J . Ocular
V I I I . DRUG TARGETING
and (c) drug delivery to the lung, liver and spleen. Two
forms of external control have been explored. Liposomes
OOI A C T I V E T A R G E T I N G I—antibody-antigen
events H h-extracorporeal guidance H I lymphotropism 1 |
capillary blockage normal capillary diameter 4 7 10
100 01 I 4 MICROSPHERE DIAMETERS (MICRONS)
IX. CONCLUSIONS
30. P . L . Car l , P . K. C h a k r a v a r t y , J . A.
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31. P . K. C h a k r a v a r t y , P . L . Car l , M. J .
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32. P . K. C h a k r a v a r t y , P . L. Ca r l , M. J .
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155. B . Pep i tp ie r re , L. P e r r i n , M. R u d h a r
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333. H. Von Hayek, The Human Lung, Hafer, New York, 1960.
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453. H. B u n d g a a r d , D r u g t a r g e t i n g : P r
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I. INTRODUCTION
Ascorbic acid
Iron preparations
Methyltestosterone
Nicotinic acid
Table 1 (Continued)
Potassium
Pyridoxine
Vitamin combinations
Acetazol amide
Ethaverine HC1
I so so r bide dinitrate
Nicotinyl alcohol
Nitroglycerin
Papaverine HC1
Pentaerythritol tetranitrate
Procainamide
Reserpine
CNS drugs
Amphetamine sulfate
Aspirin
Caffeine
Chlorpromazine
Dextroamphetamine sulfate
Diazepam
Diethylpropion HC1
Fluphenazine
Indomethacin
Lithium
Meprobamate
Orphenadrine citrate
Pentobarbital
Pentylenetetrazole
Perphenazine
Phenmetrazine HC1
Pheno barbital
Phentermine HC1
Prochlorperazine
Respiratory agents
Aminophylline
Brompheniramine maleate
Carbinoxamine maleate
[Respiratory agents]
Combination, antitussive
Combination, expectorant
Dexchlorpheniramine maleate
Dimethindene maleate
Dyphenylpraline HC1
Dyphylline
Phenylpropanolamine HC1
Theophylline
Trimeprazine
Tripelennamine HC1
Xanthine combinations
Antimicrobial
Tetracycline
Gastrointestinal drugs
Belladonna alkaloids
Hexocyclium methylsulfate
Hyoscyamine sulfate
Isopropamide iodide
Prochlorperazine maleate
Tridihexethyl chloride
Other
Pyridostigmine bromide
from Ref. 2.
lem has occupied the minds of many for a long time. For
controlled
other hand, drug reaches the liver via the portal vein at
far greater
Dosing
4. Large doses
5. Poor absorption
6. Active absorption
dose Tedra l SA
Pellets in capsules
Pellets in tab le t s
Complexation
Microencapsulation
Flotation- diffusion
V. IN VITRO CONSIDERATIONS
INSTANT RELEASE,
V I . IN VIVO CONSIDERATIONS
its unchanged form, and (d) drug release from the sustained
release
A. First-Order Release
1. Single Dose
(k r « k a ) . T k t k t"| s r el r Le - e J D k (1)
k - k n r el Eq. (1) can be converted to describe drug
concentration, C, by
dose increase.
2. Repeated Dose
the dosage interval T is less than the time taken for all
drug to be
state. These values are obtained from Eqs. (4) and (5), and
the
B . Zero-Order Release
1. Single Dose
the rate at which drug is released from the dosage form and
also the
1. Single Dose
0.17 = 27.2 mg/hr [Eq. (10)]. Substitution into Eq. (9) and
assign
desired drug level, but the level reached is only one half
the minimum
2. Repeated Dose
each dose (Figs. 8 and 9), this type of drug level pattern
cannot
increased to 8.7 and 9.2 yg/ml shortly after the second and
third
2. Single Dose
10.0
7.5 H
C(pg/ml)
5.0-^
2.) 5 -j 4 A 3 -H
component when the drug levels from the fast component are
at a
2. Repeated Dose
those described for the preceding case (Case C). For that
model
range.
V I I . BIOAVAILABILITY TESTING
of the plasma clearance (CL) of the drug and the total area
under
basis.
V I I I . CONCLUSIONS
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